Leiden University Scholarly Publications

Persistent URL of this record https://hdl.handle.net/1887/3278292

In Collections

This item can be found in the following collections:

Grievink, H.W.; Heuberger, J.A.A.C.; Huang, F.; Chaudhary, R.; Birkhoff, W.A.J.; Tonn, G.R.; ... ; Groeneveld, G.J. (2020)

DNL104, a centrally penetrant RIPK1 inhibitor, inhibits RIP1 kinase phosphorylation in a randomized phase I ascending dose study in healthy volunteers

Article / Letter to editor
Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) regulates inflammation, cytokine release, and necroptotic cell death and is implicated in pathogenic cellular pathways in amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), and multiple sclerosis. Inhibition of RIPK1 activity protects against inflammation and cell death in multiple animal models. DNL104 is a selective, brain-penetrant inhibitor of RIPK1 phosphorylation in clinical development for AD and ALS. DNL104 was tested in 68 healthy volunteers to investigate safety and tolerability, pharmacokinetic profile in plasma and cerebrospinal fluid, and pharmacodynamic effects of RIPK1 inhibition in peripheral blood mononuclear cells in a first-in-human, placebo-controlled, double-blind, randomized single-ascending dose (SAD) and multiple-ascending dose (MAD) study. DNL104 was well-tolerated in the SAD group and during the dosing period of the MAD group. However, postdose liver toxicity in 37.5% of subjects was...Show moreReceptor-interacting serine/threonine-protein kinase 1 (RIPK1) regulates inflammation, cytokine release, and necroptotic cell death and is implicated in pathogenic cellular pathways in amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), and multiple sclerosis. Inhibition of RIPK1 activity protects against inflammation and cell death in multiple animal models. DNL104 is a selective, brain-penetrant inhibitor of RIPK1 phosphorylation in clinical development for AD and ALS. DNL104 was tested in 68 healthy volunteers to investigate safety and tolerability, pharmacokinetic profile in plasma and cerebrospinal fluid, and pharmacodynamic effects of RIPK1 inhibition in peripheral blood mononuclear cells in a first-in-human, placebo-controlled, double-blind, randomized single-ascending dose (SAD) and multiple-ascending dose (MAD) study. DNL104 was well-tolerated in the SAD group and during the dosing period of the MAD group. However, postdose liver toxicity in 37.5% of subjects was observed in the MAD, and assessed to be drug related. We demonstrate that DNL104 leads to RIP1 kinase inhibition, and this is not associated with central nervous system (CNS) toxicities, supporting future development of CNS penetrant RIPK1 inhibitors.Show less
All authors
Grievink, H.W.; Heuberger, J.A.A.C.; Huang, F.; Chaudhary, R.; Birkhoff, W.A.J.; Tonn, G.R.; Mosesova, S.; Erickson, R.; Moerland, M.; Haddick, P.C.G.; Scearce-Levie, K.; Ho, C.; Groeneveld, G.J.
Date
2020-02-01
Journal
Clinical Pharmacology & Therapeutics
Volume
107
Issue
2
Pages
406 - 414
DOI
doi:10.1002/cpt.1615
Link
https://ascpt.onlinelibrary.wiley.com/doi/10.1002/cpt.1615